- Synthesis and antiproliferative screening of novel analogs of regioselectively demethylated colchicine and thiocolchicine
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Colchicine, a pseudoalkaloid isolated from Colchicum autumnale, has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, 1) and 1-demethylthiocolchicine (3), a series of 12 colchicine derivatives including 5 novel esters (2b-c and 4b-d) and 4 carbonates (2e-f and 4e- f) were synthesized. The antiproliferative activity assay, together with in silico evaluation of physicochemical properties, confirmed attractive biological profiles for all obtained compounds. The substitutions of H-donor and H-acceptor sites at C1 in thiocolchicine position provide an efficient control of the hydration affinity and solubility, as demonstrated for anhydrate 3, hemihydrate 4e and monohydrate 4a.
- Czerwonka, Dominika,Huczyński, Adam,Katrusiak, Andrzej,Maj, Ewa,Sobczak, Szymon,Wietrzyk, Joanna
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supporting information
(2020/03/17)
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- Phospholipidic Colchicinoids as Promising Prodrugs Incorporated into Enzyme-Responsive Liposomes: Chemical, Biophysical, and Enzymological Aspects
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Enzyme-responsive liposomes release their cargo in response to pathologically increased levels of enzymes at the target site. We report herein an assembly of phospholipase A2-responsive liposomes based on colchicinoid lipid prodrugs incorporated into lipid bilayer of the nanosized vesicles. The liposomes were constructed to addresses two important issues: (i) the lipid prodrugs were designed to fit the structure of the enzyme binding site; and (ii) the concept of lateral pressure profile was used to design lipid prodrugs that introduce almost no distortions into the lipid bilayer packing, thus ensuring that corresponding liposomes are stable. The colchicinoid agents exhibit antiproliferative activity in subnanomolar range of concentrations.
- Shchegravina, Ekaterina S.,Tretiakova, Daria S.,Alekseeva, Anna S.,Galimzyanov, Timur R.,Utkin, Yuri N.,Ermakov, Yuri A.,Svirshchevskaya, Elena V.,Negrebetsky, Vadim V.,Karpechenko, Natalia Yu.,Chernikov, Valery P.,Onishchenko, Natalia R.,Vodovozova, Elena L.,Fedorov, Alexey Yu.,Boldyrev, Ivan A.
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p. 1098 - 1113
(2019/03/26)
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- A Facile Synthetic Approach to Nonracemic Substituted Pyrrolo-allocolchicinoids Starting from Natural Colchicine
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A six-step semisynthetic approach towards chiral nonracemic pyrrolo-allocolchicinoids starting from naturally occurring colchicine was developed. The synthetic scheme includes an electrocyclic tropolone ring contraction to afford allocolchicinic acid followed by the Curtius reaction, giving the corresponding aniline. The Sandmeyer reaction and copper-mediated hydrazination gave hydrazine-substituted allocolchicine. This was introduced into the Fischer indole synthesis, affording libraries of regioisomeric indole-based allocolchicine congeners.
- Shchegravina, Ekaterina S.,Svirshchevskaya, Elena V.,Schmalz, Hans-Günther,Fedorov, Alexey Yu
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p. 1612 - 1622
(2019/03/26)
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- Gold-catalyzed cyclization in the synthesis of antimitotic 2,3-dihydrobenzo[b]oxepine derivatives of colchicine
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New allocolchicine derivatives bearing 2,3-dihydrobenzo[b]oxepine moiety were synthesized via gold-catalyzed cyclization as a key synthetic step. The obtained 2,3-dihydrobenzo[b]oxepine-containing allocolchicinoids possess cytotoxic activity against HEK293, PANC-1, COL0357, HeLa, and Colon26 cancer cell lines at low micromolar range of concentrations.
- Bukhvalova, S. Yu.,Maleev,Gracheva, Yu. A.,Voitovich, Yu. V.,Ignatov,Svirshchevskaya,Fedorov, A. Yu.
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p. 2205 - 2215
(2020/02/15)
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- Enantioselective total synthesis of (-)-colchicine, (+)-demecolcinone and metacolchicine: Determination of the absolute configurations of the latter two alkaloids
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Here, we describe a concise, enantioselective, and scalable synthesis of (-)-colchicine (9.2% overall yield, >99% ee). Moreover, we have also achieved the first syntheses of (+)-demecolcinone and metacolchicine, and determined their absolute configurations. The challenging tricyclic 6-7-7 core of colchicinoids was efficiently introduced using an intramolecular oxidopyrylium-mediated [5 + 2] cycloaddition reaction. Notably, the synthesized colchicinoid 23 exhibited potent inhibitory activity toward the cell growth of human cancer cell lines (IC50 = ～3.0 nM), and greater inhibitory activity towards microtubule assembly than colchicine, making it a promising lead in the search for novel anticancer agents.
- Chen, Bo,Liu, Xin,Hu, Ya-Jian,Zhang, Dong-Mei,Deng, Lijuan,Lu, Jieyu,Min, Long,Ye, Wen-Cai,Li, Chuang-Chuang
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p. 4961 - 4966
(2017/07/10)
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- Synthesis and cytostatic properties of polyfunctionalized furanoallocolchicinoids
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A series of furan-based allocolchicinoids was prepared from commercially available colchicine via a nine-step reaction sequence. Cytostatic activity, cell cycle arrest, apoptosis, tubulin and F-actin expression were studied in vitro in 2D and 3D cultures of normal and tumor epithelial keratinocytes, endothelial and mesenchymal cells. Among the prepared furanoallocolchicine analogues, 14a and 7a displayed the most pronounced anti-cancer activity. These compounds induced two types of effects: (a) cell cycle arrest in the G2/M phase as a direct consequence of effective tubulin binding (metaphase effect), and (b) pronounced cell stress (as evidenced by the overexpression of tubulin and F-actin), which was caused by the hyperpolarization of mitochondrial and lysosomal membranes (interphase effect).
- Gracheva, Iuliia A.,Voitovich, Iuliia V.,Faerman, Vladimir I.,Sitnikov, Nikolay S.,Myrsikova, Ekaterina V.,Schmalz, Hans-Gunther,Svirshevskaya, Elena V.,Fedorov, Alexey Yu
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p. 432 - 443
(2016/12/06)
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- Synthesis of new sulfur-containing derivatives of furanoallocolchicinoids
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Reaction of hydroxyl-containing heterocyclic colchicinoids with S-nucleophiles led to the formation of furanoallocolchicinoid sulfides in a high yield.
- Gracheva, Yu. A.,Schmalz,Svirshchevskaya,Fedorov, A. Yu.
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p. 1137 - 1142
(2016/10/04)
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- Colchiceine complexes with lithium, sodium and potassium salts-spectroscopic studies
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Colchiceine complexes with Li+, Na+ and K+ cations have been synthesized and studied by 1H and 13C NMR, FT-IR, FAB MS and UV-Vis. It has been shown that colchiceine forms stable complexes especially with lithium cation and the most stable structures of the complexes are those in which the acetamide groups are involved in the coordination process. The structures of the colchiceine complexes with Li+, Na+ and K+ cations are discussed in details.
- Kurek, Joanna,Barczynski, Piotr
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p. 297 - 308
(2017/01/21)
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- Synthesis and biological evaluation of furanoallocolchicinoids
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A series of conformationally flexible furan-derived allocolchicinoids was prepared from commercially available colchicine in good to excellent yields using a three-step reaction sequence. Cytotoxicity studies indicated the potent activity of two compounds against human epithelial and lymphoid cell lines (AsPC-1, HEK293, and Jurkat) as well as against Wnt-1 related murine epithelial cell line W1308. The results of in vitro experiments demonstrated that the major effect of these compounds was the induction of cell cycle arrest in the G2/M phase as a direct consequence of effective tubulin binding. In vivo testing of the most potent furanoallocolchicinoid 10c using C57BL/6 mice inoculated with Wnt-1 tumor cells indicated significant inhibition of the tumor growth.
- Voitovich, Yuliya V.,Shegravina, Ekaterina S.,Sitnikov, Nikolay S.,Faerman, Vladimir I.,Fokin, Valery V.,Schmalz, Hans-Gunther,Combes, Sebastien,Allegro, Diane,Barbier, Pascal,Beletskaya, Irina P.,Svirshchevskaya, Elena V.,Fedorov, Alexey Yu.
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supporting information
p. 692 - 704
(2015/01/30)
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- Synthesis of Colchicine C-10-Amino-Acid Derivatives
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Colchicine derivatives modified on C-10 by natural and synthetic amino acids were synthesized.
- Garazd, Ya. L.,Garazd,Kartsev
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p. 1138 - 1141
(2016/02/18)
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- Surface modified silica nanoparticles for synchronous magnetic resonance imaging and drug delivery applications
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This study reports a simple and versatile method of tailoring surface modified silica nanoparticles (SMS NPs) via co-condensation technique. The particles were loaded with gadolinium oxide and an anticancer drug, colchicine, utilizing the aqueous core of the reverse micelle as "nano" host reactors. The surface of the silica NPs was modified with 3-aminopropyltriethoxysilane. Surface modification entails higher content of the drug and allows it to get released in a sustained manner. The particles exhibit spherical morphology with an average diameter of 60 nm as measured by TEM. Gadolinium oxide is paramagnetic in nature as observed from the NMR line broadening effect on proton spectrum of the surrounding water. Preliminary in vitro experiments on MCF-7 reveal good potential of these SMS NPs for cancer therapy. It is expected that these highly versatile multifunctional silica NPs could potentially be employed for simultaneous non-invasive imaging and therapeutic purposes.
- Singh, Henam Premananda,Mitra, Susmita,Sharma, Rakesh Kumar
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p. 61028 - 61035
(2015/02/19)
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- A convenient entry to new C-7-modified colchicinoids through azide alkyne [3+2] cycloaddition: Application of ring-contractive rearrangements
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Reliable procedures for the preparation of azides derived from colchicine (1), allocolchicine (3) and N-acetylcolchinol (4a) were developed. These azides were then employed in Cu-catalyzed Huisgen-Sharpless [3+2] cycloaddition ("click") reactions with alkynes under microwave irradiation. The method developed opens a convenient and efficient access to libraries of new C-7-modified colchicinoids (triazole derivatives). In addition, a plausible mechanistic rationale for the colchicine-allocolchicine rearrangement is suggested. The Japan Institute of Heterocyclic Chemistry.
- Nicolaus, Norman,Reball, Jens,Sitnikov, Nikolay,Velder, Janna,Termath, Andreas,Fedorov, Alexey Yu.,Schmalz, Hans-Guenther
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experimental part
p. 1585 - 1600
(2011/06/17)
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- Syntheses of colchicine and isocolchicine labelled with carbon-11 or carbon-13
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The syntheses of isotopically labelled (-)-10-[11C/13C]-colchicine and (-)-9-[11C/13C]-isocolchicine have been achieved from the reaction of (-)desmethylcolchicine with [11C/13C]-iodomethane. The radiolabelled compounds, (-)-10-[11C]-colchicine (11C-n-colchicine) and (-)-9-[11C]-isocolchicine (11C-i-colchicine), were isolated by reversed phase HPLC. The total synthesis time was approximately 60 minutes for both radiolabelled compounds with an average specific activity of 240 mCi/μmol calculated to EOB. Utilizing a similar synthetic strategy, we also report the synthesis of milligram quantities of the carbon-13 enriched compounds and the magnetic resonance signal assignment for (-)-9-[13C] isocolchicine.
- Kothari,Finn,Larson
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p. 521 - 528
(2007/10/02)
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- Fluorinated colchicinoids: Antitubulin and cytotoxic properties
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The synthesis of B-ring and C-ring trifluoroacetamide-substituted colchicinoids and fluoro-substituted colchicineethylamides is presented. The B-ring trifluoroacetamido-substituted analogues exhibit moderate enhancement of potency compared to the nonfluorinated analogues for tubulin assembly inhibition and cytotoxicity toward two wild type cells lines. The C-ring substituted fluoroethylamides have reduced relative potencies in the same systems due to the strong electron-withdrawing effect of the fluoro derivatives. The fluoro colchicinoids are much more cytotoxic toward drug- resistant cell lines than to the wild type cell lines. Their enhanced potency is probably due to an effect of the fluoro moiety on functions specific to resistant cells and/or their higher hydrophobicity that may result in higher intracellular drug content. This finding may suggest the application of designed fluorinated anticancer drugs to overcome acquired resistance which may develop after several regiments of treatment with a nonfluorinated chemotherapeutic agent.
- Ringel,Jaffe,Alerhand,Boye,Muzaffar,Brossi
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p. 3334 - 3338
(2007/10/02)
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- 1-ACETAMIDO-3-(3,4,5-TRIMETHOXYPHENYL)PROPYL.
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The treatment of 4- left bracket 1-acetamido-3-(3,4,5-trimethoxyphenyl)propyl right bracket tropolone with etheral diazomethane gave the 6- and 4-substituted title compounds in 51 and 38% yields, respectively. The 270-MHz **1H-NMR spectral analysis performed on these compounds, colchicine, and two methyl ethers of hinokitiol permits unequivocal assignment of the position of the C-substituent on these 2-methoxytropone rings. Attempts were made to effect the direct B-ring closure of these intermediates and 4- left bracket 1-acetamido-3-(3,4,5-trimethoxyphenyl)propyl right bracket -5-aminotropolone using various oxidizing reagents.
- Yamamoto,Hara Atsushi,Inokawa,Nozoe
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p. 3106 - 3109
(2007/10/02)
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- Biological Effects of Modified Colchicines. Improved Preparation of 2-Demethylcolchicine, 3-Demethylcolchicine, and (+)-Colchicine and Reassignment of the Position of the Double Bond in Dehydro-7-deacetamidocolchicines
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A variety of colchicine, demecolcine, and isocolchicine derivatives were examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein.A qualitatively direct correlation was found between in vivo potency and toxicity; potency appeared to be less well correlated with tubulin binding.The most potent compounds were N-acylated analogues of colchicine and demecolcine.Among the monophenols, only 3-demethylcolchicine showed an appreciable effect in vitro and in vivo and was less toxic than colchicine.Improved methods were found for the preparation of 3- and 2-demethylcolchicine, which involved the use of 85percent phosphoric acid and concentrated sulfuric acid, respectively.Decoupling experiments with 1H NMR proved that the double bond of dehydro-7-deacetamidocolchiceine and its derived tropolonic methyl ethers 24 and 25 was in the 5,6 position, rather than the 6,7 position formerly tentatively assigned.
- Roesner, Manfred,Capraro, Hans-Georg,Jacobson, Arthur E.,Atwell, Louise,Brossi, Arnold,et al.
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p. 257 - 261
(2007/10/02)
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